CN103450132A - 一类新颖的磺胺-香豆素衍生物的合成及制备方法 - Google Patents
一类新颖的磺胺-香豆素衍生物的合成及制备方法 Download PDFInfo
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Abstract
一类磺胺-香豆素衍生的合成方法及制备,其特征是它有如下通式:
Description
发明内容
本发明的目的在于提供一类新颖的含磺胺-香豆素衍生的合成及制备方法
背景技术
磺胺类药物具有多种生物活性,一直是药物化学领域研究的热点,在抗菌、降血压、利尿等方面有广泛应用,但是,该类药物是抑菌剂,而无杀菌作用,易产生耐药性以及经常使用会产生许多不良反应,从而使其应用范围受到了极大的限制.但是由于其易产生抗药性,使用范围已逐渐减小.但是近年来的文献多次报道了其衍生物的具有除抗菌外其他方面的活性,其中最显著的是抗肿瘤活性.
此外,香豆素类化合物是一类重要的有机杂环化合物,具有抗菌、消毒、抗凝和抗肿瘤等多种生理活性,已广泛应用于医药行业.在香豆素基本骨架的基础上进行结构修饰,所得的衍生物可用作镇痛、杀虫、降血压、抗血栓及抗癌等药物.香豆素(coumarins)分为简单香豆素包括双分子和三分子香豆素的聚合物,呋喃香豆素、吡喃香豆素,简单香豆素一般具有抗炎、消肿、解痉挛、镇静、抗菌等作用.许多植物中都含有香豆素,包括豆类、薰衣草、甘草、草莓、杏、樱桃、肉桂和草木樨等.香豆素类药物体内代谢物对齿类动物具有毒副作用,曾受到质疑,但近年发现天然香豆素类化合物具有抗HIV病毒及抗癌等活性,又受到关注并得到较快发展.
基于此,本发明将不同香豆素引入到磺胺衍生物中,设计合成合成了一系列结构新颖的磺胺香豆素衍生物,期望具有更好的生物活性、更高的选择性、更低的毒性、更长或更短的残效期等.
发明内容
本发明的技术方案如下:
1.一类磺胺-香豆素衍生的合成及制备,其特征是它有如下通式:
一种上述的磺胺-香豆素衍生的合成,它由下列步骤组成:
步骤1.在反应容器中加入适量的N,N-二甲基甲酰胺(DMF),然后在所需的低温下,慢慢加入三氯氧磷,继续搅拌5min后加入含香豆素衍生物的DMF溶液,慢慢使其恢复室温,继续搅拌反应一段时间后,将该反应转移至恒定温度的容器中,继续搅拌反应(TLC跟踪反应,直至至少一种原料很少甚至没有),待反应结束后,将其倒入冷水中,用碱调其溶液到一定pH值时,会有大量固体析出,采用某种方法得到目标化合物2.
步骤2.在反应容器中加入适量香豆素醛的衍生物和适量的有机溶剂,在一定温度下搅拌使之溶解,然后按适量比例加入磺胺的衍生物,再滴加少量的酸,在适当的温度搅拌反应一段时间(TLC跟踪反应,直至至少一种原料很少甚至没有),蒸去有机溶剂、向反应物中加适量的水或直接过滤得粗产品,粗品经柱层析或采用适当的有机溶剂重结晶提纯得目标化合物3.
具体实施方式
实施例一:4-氯-3-甲酰基-6,8-二叔丁基香豆素(化合物2)的制备
在0℃下依次将DMF(20mL)、三氯氧磷(10mL)加入到100mL圆底烧瓶中搅拌,在0℃下加入4-羟基-6,8-二叔丁基香豆素(4.0g,14.6mmol)的DMF溶 液(10mL),让反应液在0℃下搅拌反应2h,然后将该反应转移至55℃的油浴锅中继续搅拌反应1h后(TLC跟踪反应;展开剂:V二氯甲烷∶V乙酸乙酯=1∶6),将反应液倒入到冰浴中,用固体Na2CO3调溶液pH至中性,有大量固体析出,抽滤,烘干,得到化合物2的橘黄色固体3.4g,产率72.8%.m.p.134~136℃;1H NMR(DMSO-d6,300MHz)δ:10.35(s,1H,COH),8.44~8.25(m,2H,ArH),1.54(s,9H,C(CH3)3),1.42(s,9H,C(CH3)3).
实施例二:4-(4-氯-2-酮-2H-3-甲醛)缩-苯磺酰胺(化合物3)的制备
在搅拌下依次将化合物4-氯-3-甲酰基香豆素(0.25g,1.2mmol)、乙醇(15mL)、磺胺(0.19g,1.2mmol),冰乙酸(0.3mL)加入到25mL的圆底烧瓶中,在50℃下加热8h(TLC监测反应;展开剂:V二氯甲烷∶V乙酸乙酯=1∶1),在反应结束后,减压除去部分溶剂,加入少量蒸馏水,过滤,烘干得橘黄色色固体0.34g,产率79.0%.m.p.271~273℃;1H NMR(DMSO-d6,300MHz)δ:11.78(s,1H,SO2NH),10.05(s,1H,CH),7.89~7.07(m,8H,ArH),3.80(s,2H,NH).
实施例三:4-(4-氯-2-酮-2H-3-甲醛)缩-磺胺噻唑(化合物4)的制备
制备方法同实施例二以磺胺噻唑代替磺胺,得到橘黄色目标化合物.产率73.4%.m.p.276~278℃;1H NMR(DMSO-d6,300MHz)δ:11.68(s,1H,SO2NH),9.61(s,1H,-CH),8.89~7.69(m,8H,ArH),7.30(s,J=2.7Hz,1H,-CH),6.89(s,J=2.7Hz,1H,-CH),6.90(s,1H,NH).
实施例四:4-(4-氯-2-酮-2H-3-甲醛)缩-磺胺胍(化合物5)的制备
制备方法同实施例二.以磺胺胍代替磺胺,得到橘黄色目标化合物.产率65.6%.m.p.261~262℃;1H NMR(DMSO-d6,300MHz)δ:11.70(s,1H,SO2NH),10.01(s,1H,-CH),7.82~7.06(m,8H,ArH),6.76(s,4H,NH).
实施例五:4-(4-氯-2-酮-2H-3-甲醛)缩-磺胺二甲基嘧啶(化合物6)的制备
制备方法同实施例二.以磺胺二甲基嘧啶代替磺胺,得到橘黄色目标化合物.产率62.2%.m.p.245~247℃;1H NMR(DMSO-d6,300MHz)δ:11.65(s,1H,SO2NH),9.63(s,1H,CH),9.01(s,1H,CH),8.94~7.33(m,8H,ArH),2.24(s,6H,CH3).
实施例六:4-(4-氯-2-酮-2H-3-甲醛)缩-磺胺甲噁唑(化合物7)的制备
制备方法同实施例二.以磺胺甲噁唑代替磺胺,得到橘黄色目标化合物.产率63.1%.m.p.245~247℃;1H NMR(DMSO-d6,300MHz)δ:11.73(s,1H,SO2NH),9.61(s,1H,CH),8.96~7.44(m,8H,ArH),6.2(s,J=0.8Hz,1H,-CH),2.29(s,6H,CH3).
实施例七:4-(4-氯-2-酮-2H-3-甲醛)缩-磺胺甲基嘧啶(化合物8)的制备
制备方法同实施例二.以磺胺甲基嘧啶代替磺胺,得到橘黄色目标化合物.产率87.9%.m.p.245~247℃;1H NMR(DMSO-d6,300MHz)δ:11.68(s,1H,SO2NH),9.64(s,1H,CH),9.04(s,J=5.2Hz,1H,CH),8.68~7.47(m,8H,ArH),6.86(d,J=5.2Hz,1H,-CH),2.31(s,3H,CH3).
实施例八:4-(4-氯-2-酮-2H-6,8-二叔丁基-3-甲醛)缩-苯磺胺(化合物9)的制备
制备方法同实施例二.以4-氯-3-甲酰基-6,8-二叔丁基香豆素代替4-氯-3-甲 酰基-香豆素,得到橘黄色目标化合物.产率44.8%.m.p.>300℃;1H NMR(DMSO-d6,300MHz)δ:9.61(s,1H,CH),7.64(s,2H,NH),8.81~7.66(m,6H,ArH),1.52(s,9H,C(CH3)3),1.40(s,9H,C(CH3)3).
实施例九4-(4-氯-2-酮-2H-6,8-二叔丁基-3-甲醛)缩-苯磺酰胺噻唑(化合物10)的制备
制备方法同实施例三.以4-氯-3-甲酰基-6,8-二叔丁基香豆素代替4-氯-3-甲酰基-香豆素,得到橘黄色目标化合物.产率87.8%.m.p.>300℃;1H NMR(DMSO-d6,300MHz)δ:11.74(s,1H,SO2NH),9.61(s,1H,-CH),8.86~7.65(m,6H,ArH),7.28(s,J=2.7Hz,1H,CH),6.88(s,J=2.7Hz,1H,CH),6.90(s,1H,NH),1.50(s,9H,C(CH3)3),1.39(s,9H,C(CH3)3).
实施例十4-(4-氯-2-酮-2H-6,8-二叔丁基-3-甲醛)缩-苯磺酰胺胍(化合物11)的制备
制备方法同实施例四.以4-氯-3-甲酰基-6,8-二叔丁基香豆素代替4-氯-3-甲酰基-香豆素,得到橘黄色目标化合物.产率70.0%.m.p.286~288℃;1H NMR(DMSO-d6,300MHz)δ:11.77(s,1H,SO2NH),9.52(s,1H,CH),8.77~7.66(m,6H,ArH),6.80(s,3H,NH),1.51(s,9H,C(CH3)3),1.39(s,9H,C(CH3)3).
实施例十一4-(4-氯-2-酮-2H-6,8-二叔丁基-3-甲醛)缩-苯磺酰胺二甲基嘧啶(化合物12)的制备
制备方法同实施例五.以4-氯-3-甲酰基-6,8-二叔丁基香豆素代替4-氯-3-甲酰基-香豆素,得到橘黄色目标化合物.产率50.8%.m.p.140~142℃;1H NMR (DMSO-d6,300MHz)δ:11.76(s,1H,SO2NH),9.63(s,1H,CH),9.01(s,1H,CH),8.94~7.33(m,8H,ArH),2.24(s,6H,CH3).1.51(s,9H,C(CH3)3),1.39(s,9H,C(CH3)3).
实施例十二4-(4-氯-2-酮-2H-6,8-二叔丁基-3-甲醛)缩-苯磺酰胺甲噁唑(化合物13)的制备
制备方法同实施例六.以4-氯-3-甲酰基-6,8-二叔丁基香豆素代替4-氯-3-甲酰基-香豆素,得到橘黄色目标化合物.产率63.1%.m.p.217~219℃;1H NMR(DMSO-d6,300MHz)δ:11.68(s,1H,SO2NH),9.65(s,1H,-CH),8.96~7.44(m,8H,ArH),6.23(s,J=0.8Hz,1H,CH),2.29(s,6H,CH3).1.53(s,9H,C(CH3)3),1.41(s,9H,C(CH3)3).
实施例十三:4-(4-氯-2-酮-2H-6,8-二叔丁基-3-甲醛)缩-磺胺甲基嘧啶(化合物14)的制备
制备方法同实施例七.以磺胺甲基嘧啶代替磺胺,得到橘黄色目标化合物.产率87.9%.m.p.245~247℃;1H NMR(DMSO-d6,300MHz)δ:11.66(s,1H,SO2NH),9.64(s,1H,CH),9.04(s,J=5.2Hz,1H,CH),8.68~7.47(m,8H,ArH),6.86(d,J=5.2Hz,1H,CH),2.31(s,3H,CH3),1.53(s,9H,C(CH3)3),1.41(s,9H,C(CH3)3).
实施例十四4-(4-氯-2-酮-2H-6-甲基-3-甲醛)缩-苯磺酰胺甲噁唑(化合物15)的制备
制备方法同实施例二.以4-氯-3-甲酰基-6-甲基香豆素代替4-氯-3-甲酰基-香豆素,得到橘黄色目标化合物.产率57.2%.m.p.>300℃;1H NMR(DMSO-d6, 300MHz)δ:11.71(s,1H,SO2NH),9.54(s,1H,CH),8.80~7.29(m,7H,ArH),2.45(s,3H,CH3).
实施例十五4-(4-氯-2-酮-2H-6-甲基-3-甲醛)缩-苯磺酰胺噻唑(化合物16)的制备
制备方法同实施例三.以4-氯-3-甲酰基-6-甲基香豆素代替4-氯-3-甲酰基-香豆素,得到橘黄色目标化合物.产率57.8%.m.p.225~227℃;1H NMR(DMSO-d6,300MHz)δ:11.62(s,1H,SO2NH),9.56(s,1H,-CH),8.86~7.45(m,6H,ArH),7.32(s,J=5.0Hz,1H,-CH),7.29(s,1H,ArH),6.90(s,J=5.0Hz,1H,-CH),6.90(s,1H,NH),2.43(s,3H,CH3).
实施例十六4-(4-氯-2-酮-2H-6-甲基-3-甲醛)缩-苯磺酰胺胍(化合物17)的制备
制备方法同实施例四.以4-氯-3-甲酰基-6-甲基香豆素代替4-氯-3-甲酰基-香豆素,得到橘黄色目标化合物.产率50.0%.m.p.250~252℃;1H NMR(DMSO-d6,300MHz)δ:11.59(s,1H,SO2NH),9.52(s,1H,CH),7.83~7.23(m,6H,ArH),6.77(s,3H,NH),2.39(s,3H,CH3).
实施例十七4-(4-氯-2-酮-2H-6-甲基-3-甲醛)缩-苯磺酰胺二甲嘧啶(化合物18)的制备
制备方法同实施例五.以4-氯-3-甲酰基-6-甲基香豆素代替4-氯-3-甲酰基-香豆素,得到橘黄色目标化合物.产率50.7%.m.p.170~172℃;1H NMR(DMSO-d6,300MHz)δ:11.59(s,1H,SO2NH),9.58(s,1H,CH),8.98~7.28(m,8H,ArH),6.70(s,1H,CH),2.42(s,3H,CH3),2.23(s,6H,CH3).
实施例十八4-(4-氯-2-酮-2H-6-甲基-3-甲醛)缩-苯磺酰胺甲噁唑(化合物19)的制 备
制备方法同实施例六.以4-氯-3-甲酰基-6-甲基香豆素代替4-氯-3-甲酰基-香豆素,得到橘黄色目标化合物.产率54.6%.m.p.240~242℃;1H NMR(DMSO-d6,300MHz)δ:11.78(s,1H,SO2NH),9.51(s,1H,CH),8.88~7.33(m,7H,ArH),6.23(s,J=0.9Hz,1H,CH),2.36(s,3H,CH3).2.22(s,3H,CH3).
实施例十九4-(4-氯-2-酮-2H-6-甲基-3-甲醛)缩-苯磺酰胺甲基嘧啶(化合物20)的制备
制备方法同实施例七.以4-氯-3-甲酰基-6-甲基香豆素代替4-氯-3-甲酰基-香豆素,得到橘黄色目标化合物.产率73.8%.m.p.273~275℃;1H NMR(DMSO-d6,300MHz)δ:11.76(s,1H,SO2NH),9.64(s,1H,CH),9.97(d,J=2.0Hz,1H,CH),8.42~7.32(m,7H,ArH),6.78(d,J=5.2Hz,1H,-CH),2.44(s,3H,CH3),2.27(s,3H,CH3) 。
Claims (1)
- 本发明的技术方案如下:1.一类磺胺-香豆素衍生的合成及制备,其特征是它有如下通式:一种上述的磺胺-香豆素衍生的合成,它由下列步骤组成:步骤1.在反应容器中加入适量的N,N-二甲基甲酰胺(DMF),然后在所需的低温下,慢慢加入三氯氧磷,继续搅拌5min后加入含香豆素衍生物的DMF溶液,慢慢使其恢复室温,继续搅拌反应一段时间后,将该反应转移至恒定温度的容器中,继续搅拌反应(TLC跟踪反应,直至至少一种原料很少甚至没有),待反应结束后,将其倒入冷水中,用碱调其溶液到一定pH值时,会有大量固体析出,采用某种方法得到目标化合物2.步骤2.在反应容器中加入适量香豆素醛的衍生物和适量的有机溶剂,在一定温度下搅拌使之溶解,然后按适量比例加入磺胺的衍生物,再滴加少量的酸,在适当的温度搅拌反应一段时间(TLC跟踪反应,直至至少一种原料很少甚至没有),蒸去有机溶剂、向反应物中加适量的水或直接过滤得粗产品,粗品经柱层析或采用适当的有机溶剂重结晶提纯得目标化合物3。
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CN104926821A (zh) * | 2015-07-10 | 2015-09-23 | 南京大学 | 含苯基磺酰基或烷基磺酰基的香豆素并吡唑衍生物制备与在抑制肿瘤中的应用 |
CN105061442A (zh) * | 2015-07-10 | 2015-11-18 | 南京大学 | 含磺酰基哌嗪的香豆素并吡唑类化合物及其制备与在抑制肿瘤细胞中的应用 |
CN106187985A (zh) * | 2016-07-18 | 2016-12-07 | 新乡医学院 | 具有抗乳腺癌活性的苯并香豆素类化合物及其制备方法 |
CN106187985B (zh) * | 2016-07-18 | 2018-10-02 | 新乡医学院 | 具有抗乳腺癌活性的苯并香豆素类化合物及其制备方法 |
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